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Clinical Study in Over 4,000 Subjects Finds Blood TMAO Levels Linked to Increased Risk of Heart Disease, Even In the Absence of Known Cardiovascular Risks

April 24, 2013

A microbial byproduct of intestinal bacteria contributes to heart disease and serves as an accurate screening tool for predicting future risks of heart attack, stroke and death in persons not otherwise identified by traditional risk factors and blood tests, according to Cleveland Clinic research published today in The New England Journal of Medicine.

The research team was led by Stanley Hazen, MD, Ph D, Vice Chair of Translational Research, Chair of the Department of Cellular and Molecular Medicine for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic, and W.H. Wilson Tang, MD, Department of Cardiovascular Medicine in the Miller Family Heart and Vascular Institute and Lerner Research Institute.

The current study is an extension of Dr. Hazen’s previous work, in which he found that a chemical byproduct called trimethylamine N-oxide (TMAO) is produced when intestinal bacteria digest the nutrient phosphatidylcholine, commonly known as lecithin. The prior research showed that TMAO levels in the blood were associated with heart disease. Dr. Hazen and colleagues have now confirmed that gut flora are essential in forming TMAO in humans and demonstrated a relationship between TMAO levels and future cardiac events like heart attack, stroke, and death—even in those with no prior evidence of cardiac disease risk.

To demonstrate the role of gut flora in forming TMAO, human subjects were asked to eat two hard-boiled eggs (a common dietary source of lecithin) and a capsule of labeled lecithin (as a tracer). After ingestion, TMAO levels in the blood increased. However, when these same subjects were given a brief course of broad-spectrum antibiotics to suppress their gut flora, their TMAO levels were suppressed, and no additional TMAO was formed, even after ingesting lecithin. These results demonstrated that the intestinal bacteria are essential for the formation of TMAO.

In the second phase of the study, the researchers measured TMAO levels in a large, independent, clinical cohort – consisting of more than 4,000 adults undergoing cardiac evaluation at the Cleveland Clinic – over a three-year follow-up period. They found that higher TMAO blood levels were associated with higher future risks of death and nonfatal heart attack or stroke over the ensuing three-year period, independent of other risk factors and blood test results. These results complement those of another recent study of Dr. Hazen’s linking gut flora metabolism of a structurally similar nutrient found in animal products, carnitine, to TMAO production and heart attack risk.

“Heart disease remains the No. 1 killer, and while we know how to reduce cholesterol, treat blood pressure, and reduce cardiac risks through diet and other interventions, a substantial residual risk still remains,” Dr. Hazen said. “We need to find new pathways to attack heart disease, and these findings strongly suggest that further research into the involvement of gut microbiome in the development of cardiovascular disease could lead to new avenues of prevention and treatment of heart disease.”

Dr. Hazen further suggested, “These studies show that measuring blood levels of TMAO could serve as a powerful tool for predicting future cardiovascular risk, even for those without known risk factors. More studies are needed to confirm that TMAO testing, like cholesterol, triglyceride or glucose levels, might help guide physicians in providing individualized nutritional recommendations for preventing cardiovascular disease. Our goal is not to suggest dietary restrictions of entire food groups. Eggs, meat and other animal products are an integral part of most individuals’ diets. Our work shows, however, that when digesting these foods, gut flora can generate a chemical mediator, TMAO, that may contribute to cardiovascular disease.” This research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements, Grant Numbers (R01HL103866, 1P20HL113452, P01HL098055, P01HL076491, R01HL103931, and R01DK080732). Cleveland Clinic has a licensing agreement with a diagnostic company to develop and commercialize a blood test for cardiovascular disease based upon the gut flora metabolite, TMAO. Dr. Hazen is listed as a co-investigator on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics. He also is a paid consultant to the company and has received royalty payments for technology that he developed.

About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S.News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. More than 3,000 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. The Cleveland Clinic health system includes a main campus near downtown Cleveland, more than 75 Northern Ohio outpatient locations, including 16 full-service Family Health Centers, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and, currently under construction, Cleveland Clinic Abu Dhabi. In 2012, there were 5.1 million outpatient visits throughout the Cleveland Clinic health system and 157,000 hospital admissions. Patients came for treatment from every state and from more than 130 countries. Visit us at http://www.clevelandclinic.org. Follow us at http://www.twitter.com/ClevelandClinic.

About the Lerner Research Institute

The Lerner Research Institute (LRI) is home to laboratory, translational and clinical research at Cleveland Clinic. Its three-part mission is: to promote human health by investigating the causes of disease and discovering new approaches to prevention and treatments, to train the next generation of biomedical researchers and to foster collaborations with clinical care providers. LRI’s total annual research expenditure was $255 million in 2012 (nearly $110 million in federal funding). With more than 700,000 square feet of lab, office, and core services space, LRI is home to more than 2,000 people working in disease-focused research programs. In 2012, LRI researchers published over 600 articles in high-impact biomedical journals (top 10 percent) and generated 83 invention disclosures, 10 new licenses and 35 patents. LRI faculty oversee curriculum and teach courses in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University and participate in doctoral programs, including the Molecular Medicine PhD Program, supported in part by the Howard Hughes Medical Institute.